Public Release: 13-Mar-2008
JCI online early table of contents: March 13, 2008

EDITOR'S PICK: High levels of the molecule adenosine linked to priapism

Priapism (prolonged penile erection in the absence of sexual interest) is common in male individuals with sickle cell disease (SCD), a blood disorder characterized by abnormally shaped red blood cells. Priapism is considered a medical emergency because it is associated with decreased blood flow to the erectile tissue, which can result in erectile tissue damage and, subsequently, erectile dysfunction and impotence. However, the development of effective treatment and prevention approaches has been limited by poor understanding of the molecular mechanisms underlying the condition. Some insight into this has now been provided by Yang Xia and colleagues, at the University of Texas Medical School at Houston, who have shown that male mice lacking the protein ADA, which breaks down the molecule adenosine, exhibit priapism that could be corrected by ADA therapy. Further analysis indicated that high levels of adenosine induced priapism through stimulation of the A2B adenosine receptor in ADA-deficient mice. As increased adenosine signaling through the A2B adenosine receptor was also shown to contribute to priapism in SCD transgenic mice, which are a well-accepted mouse model of the condition, the authors suggested that approaches to either reduce adenosine levels or block A2B adenosine receptor activation might provide new ways to treat priapism.

Cryptorchidism, the absence in the scrotum of one or both testes (usually because of the failure of the testis to descend), and hypospadias, the abnormal positioning of the opening of the urethra, are common birth defects of the male genitalia and are risk factors for the adult-onset disorders of low sperm count and testicular cancer. Although it is known that "male" hormones, in particular testosterone, drive the pathway that leads to a fetus becoming a male (including the development of the male genitalia), the cause of defects in this process is unclear. However, Michelle Welsh and colleagues at The Queen's Medical Research Institute, United Kingdom, have now determined that in rats, the "male" hormones drive the decision to become a male during a window of time before the male genitalia develop. During this period of time, blocking the action of "male" hormones led to cryptorchidism and hypospadias, and these defects were associated with a decrease in the distance between the anus and the genitalia (AGD). Based on the timing in rats, the authors believe that the equivalent window in humans is likely to be 8-14 weeks of gestation. Furthermore, they suggest that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders (cryptorchidism and hypospadias, and low sperm count and testicular cancer, respectively).

TITLE: Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism

Multiple sclerosis (MS) is a chronic inflammatory disease of the brain and spinal cord. Individuals with MS develop progressive neurological disability, and this is thought to be caused by degradation of the nerve cells. It is therefore hoped that treatments that protect nerve cells might help individuals with the progressive form of MS. Data to support this hypothesis has now been generated using a chronic progressive EAE mouse model of MS by Howard Weiner and colleagues at the Brigham and Women's Hospital, Harvard Medical School, Boston.

In the study, treatment of mice after the onset of disease with a water-soluble agent known as ABS-75, which has antioxidant properties and blocks the stimulation of the subset of nerve cells that express the NMDA receptor, markedly reduced disease progression. This beneficial effect was associated with decreased nerve cell degradation, and a similar protective effect was observed for ABS-75 when it was added to cultured nerve cells exposed to damaging reagents. These data led the authors to suggest that agents similar to ABS-75 might provide a new approach to treating individuals with MS and other neurodegenerative disorders.

TITLE: Reversal of axonal loss and disability in a mouse model of progressive multiple sclerosis

For a tumor to grow and transfer to new sites it must induce the growth of new blood vessels that deliver it nutrients and enable it to disseminate to new sites. This process is known as neovascularization, and recent evidence has suggested that mobilization of cells known as endothelial progenitor cells (EPCs) from the bone marrow might be crucial for neovascularization in several cases. Now, data generated by a team of researchers from Chittaranjan National Cancer Institute, India, and the Mayo Clinic, Rochester, has determined that a chemical known to be involved in transmitting signals from nerve cells (dopamine; DA) regulates EPC mobilization from the bone marrow in mice.

In the study decreased levels of DA in the bone marrow were associated with increased mobilization of EPCs in mice bearing tumors known as sarcomas and administration of DA inhibited this mobilization. The ability of DA to inhibit EPC mobilization from the bone marrow was mediated via the DA D2 receptor expressed by the EPCs. These data led the authors to suggest that DA as well as DA D2 receptor agonists, which are widely used in the clinic for the treatment of several conditions including Parkinson disease, might provide new approaches to the treatment of cancer.

AUTOIMMUNITY: A new road to the autoantibodies that characterize lupus

Systemic lupus erythematosus (SLE), commonly known as lupus, is a chronic autoimmune disease characterized by the inflammatory destruction of many organs, including the skin, joints, and kidneys. A hallmark of the disease is the production of IgG antibodies that target nucleic acid-associated proteins in the nucleus of the individual's own cells (so called autoantibodies). A new study, by Paul Utz and colleagues at Stanford University, has now characterized a new pathway by which immune cells known as B cells can be stimulated to produce these IgG autoantibodies in a mouse model of SLE. Specifically, signaling downstream of B cell recognition of soluble factors known as type I IFNs was found to be required for the production of IgG autoantibodies. Further, these signaling pathways were also required to upregulate the expression of two sensors of the nucleic acid-associated proteins recognized by these IgG autoantibodies (TLR7 and TLR9), an event that stimulates production of IgG autoantibodies. The authors therefore suggested that their data provide a clear rationale for pursuing the development of specific inhibitors of type I IFNs and TLRs for the treatment of individuals with SLE, therapies that are currently in preclinical and/or early-stage clinical trials.

TITLE: IRF9 and STAT1 are required for IgG autoantibody production and B cell expression of TLR7 in mice

Ovarian cancer is the fifth leading cause of death from cancer for women in the US. Ovarian tumors transfer to new sites (metastasize) differently from many other tumors -- tumor cells are simply released into the fluid that surrounds all the organs in the abdomen and are then able to generate tumors by attaching to new surfaces that support their growth. The membrane that lines the abdomen (the peritoneum) and a large fat pad between the stomach and the small intestine (the omentum) are the most common metastatic sites for ovarian tumors. Determining the molecules and mechanisms involved in the attachment of ovarian tumor cells to these sites is therefore critical for the development of therapeutics. New data, generated by Ernst Lengyal and colleagues at the University of Chicago, have indicated a key role for the protein MMP-2 in this process, leading to the suggestion that some women with ovarian cancer might benefit from early treatment with an MMP inhibitor.

In the study, expression of MMP-2 was upregulated in human ovarian tumor cells when they attached to stromal cells in culture. Further, inhibition of MMP-2 function reduced the attachment of human ovarian tumor cells in a 3D model of metastatic ovarian tumor cell attachment, and reduced their attachment to full human omentum or peritoneum in vitro and to mouse peritoneum and omentum in vivo. Of potential clinical importance, inhibition of MMP-2 function, prior to the dissemination of ovarian tumor cells through the fluid in the abdomen, in immunocompromised mice markedly decreased tumor growth and metastasis and extended survival.

TITLE: The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin

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